The ontogenetic mechanisms that are responsible for the adult patterns of innervation and function within the mammalian cochlea are poorly understood. The goal of this application is to investigate the mechanisms which underlie efferent synaptogenesis, specifically, the development of olivocochlear (OC) synapses. An additional goal is to test the generality of current models of synaptogenesis and competition in the maturation of the OC system, and ultimately, of auditory function. Since OC neurons demonstrate best frequency responses, are involved with the detection of signals in noise, and appear morphologically mature before the onset of hearing, understanding their development may help us understand hearing and disorders associated with hearing in preterm and newborn infants. The specific aims are to test the following hypotheses: 1) medial OC neurons exhibit a developmental waiting period, that is, they send projections to the cochlea that synapse on intermediate targets, 2) medial OC neurons are capable of releasing acetylcholine prior to synapsing or outer hair cells, and 3) lateral OC neurons undergo a separate period of cochlear synaptogenesis from medial OC neurons. These investigations focus primarily on the first postnatal week in newborn hamsters and gerbils and include a variety of approaches such as: retrograde and anterograde labeling to visualize the temporal sequence of efferent projections as well as synaptic input to the efferent neurons; serial-section electron microscopy of labeled efferent terminals; histochemical, immunochemical, and in situ hybridization studies of the expression of neurotransmitters and developmental markers; and characterization of enzyme activity to assess neurotransmitter mechanisms. Importantly, this research should generate specific models that can be tested by experimental interventions.